Efficacy and Safety of Plasma Exchange as an Adjunctive Therapy for Rapidly Progressive IgA Nephropathy and Henoch-Schönlein Purpura Nephritis: A Systematic Review

Patients with IgA nephropathy (IgAN), including Henoch-Schönlein purpura nephritis (HSP), who present with rapidly progressive glomerulonephritis (RPGN) have a poor prognosis despite aggressive immunosuppressive therapy. The utility of plasmapheresis/plasma exchange (PLEX) for IgAN/HSP is not well established. This systematic review aims to assess the efficacy of PLEX for IgAN and HSP patients with RPGN. A literature search was conducted using MEDLINE, EMBASE, and through Cochrane Database from inception through September 2022. Studies that reported outcomes of PLEX in IgAN or HSP patients with RPGN were enrolled. The protocol for this systematic review is registered with PROSPERO (no. CRD42022356411). The researchers systematically reviewed 38 articles (29 case reports and 9 case series articles) with a total of 102 RPGN patients (64 (62.8%) had IgAN and 38 (37.2%) had HSP). The mean age was 25 years and 69% were males. There was no specific PLEX regimen utilized in these studies, but most patients received at least 3 PLEX sessions that were titrated based on the patient’s response/kidney recovery. The number of PLEX sessions ranged from 3 to 18, and patients additionally received steroids and immunosuppressive treatment (61.6% of patients received cyclophosphamide). Follow-up time ranged from 1 to 120 months, with the majority being followed for at least 2 months after PLEX. Among IgAN patients treated with PLEX, 42.1% (n = 27/64) achieved remission; 20.3% (n = 13/64) achieved complete remission (CR) and 18.7% (n = 12/64) partial remission (PR). 60.9% (n = 39/64) progressed to end-stage kidney disease (ESKD). Among HSP patients treated with PLEX, 76.3% (n = 29/38) achieved remission; of these, 68.4% (n = 26/38) achieved CR and 7.8% achieved (n = 3/38) PR. 23.6% (n = 9/38) progressed to ESKD. Among kidney transplant patients, 20% (n = 1/5) achieved remission and 80% (n = 4/5) progressed to ESKD. Adjunctive plasmapheresis/plasma exchange with immunosuppressive therapy showed benefits in some HSP patients with RPGN and possible benefits in IgAN patients with RPGN. Future prospective, multi-center, randomized clinical studies are needed to corroborate this systematic review’s findings.


Introduction
IgA Nephropathy (IgAN), characterized by mesangial accumulation of IgA in kidney biopsy, is the most common type of primary glomerular disease and remains a leading cause of end-stage kidney disease (ESKD) in the world with an estimated incidence of 2.5 per 100,000 persons worldwide [1][2][3][4][5]. The overall prevalence of kidney biopsy-proven IgAN ranges from 4 to 44%, depending on the biopsy criterion and patient descent; the strongest predilection is towards Southeast Asians [1,6,7]. Although synpharyngitic macroscopic hematuria is well recognized as a clinical hallmark of IgAN, the most common initial symptoms in adult patients are microscopic hematuria and/or proteinuria [4,6,8]. The pathophysiology of IgAN is currently considered to be from a multi-"hit" process influenced by genetic and environmental factors [6], resulting in the presence of IgG autoantibodies and galactose-deficient IgA1 circulating immune complexes that deposit in the kidney mesangium. This activates the alternative complement pathway, local inflammation, glomerulosclerosis, and tubulointerstitial fibrosis, resulting in the loss of kidney function [6]. The disease course of IgAN is variable but often slowly progressive; about 25% of cases progress to ESKD within 10 years and about 40% progress within 20 years [9]. The risk of ESKD progression is greater in patients of Southeast Asian descent and those with preexisting risk factors of hypertension, diabetes mellitus, and proteinuria than in patients with different backgrounds [10,11].
IgA vasculitis, also known as Henoch-Schönlein purpura (HSP), is a systemic vasculitis characterized by IgA immune complex deposition within the blood vessels of the affected tissue. HSP is the most prevalent form of vasculitis in children, presenting as rashes, joint pain, gastrointestinal symptoms, and kidney disease. It is usually self-limiting in children but more severe in adults. Kidney biopsy in HSP-associated IgA nephropathy is indistinguishable from that seen in IgAN [4,12,13]. Even though HSP results in greater organ involvement, the risk of ESKD in adults with HSP-associated IgAN is comparable to that of IgAN [14].
To date, the 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines for glomerulonephritis recommends the use of angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin receptor blockers (ARB) as first-line therapy for the management of all IgAN patients with hypertension or significant proteinuria. Immunosuppressants should be used only if patients remain at high risk for the progression of chronic kidney disease (CKD) despite maximal supportive care or in patients with rapidly progressive glomerulonephritis (RPGN), which is defined as a ≥50% decline in estimated glomerular filtration rate (eGFR) within 3 months. Treatment options to mitigate ESKD progression are still limited for IgAN with crescentic disease [2].
Plasmapheresis or plasma exchange (PLEX) is a therapeutic procedure involving the extracorporeal removal or exchange of blood plasma, which includes its components of antibodies and circulating antigen-antibody complexes [15,16]. PLEX has been beneficial in the treatment of crescentic glomerulonephritis or RPGN due to anti-glomerular basement membrane (GBM) antibody disease and ANCA-associated vasculitis (AAV) [17,18]. Since the pathophysiology of IgAN includes circulating immune complexes, the use of PLEX as adjunctive therapy for IgAN with RPGN could theoretically be advantageous. According to the American Society for Apheresis 2019 guidelines, the role of PLEX may be considered individually in the treatment of IgAN and HSP with rapidly progressive/crescentic (recommendation category III) disease. However, this recommendation is weak due to the lack of randomized/prospective data regarding PLEX use [19]. Thus, this systematic review aims to consolidate existing data and assess the efficacy and safety of PLEX for the treatment of IgAN and HSP-associated IgAN patients with RPGN.

Information Sources and Search Strategy
The protocol for this systematic review is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42022356411). A systematic literature search was conducted utilizing Ovid Medline, EMBASE, the Cochrane Central Register of Controlled Trials (CCTR), and the Cochrane Database of Systematic Reviews (CDSR) from inception through September 2022 to identify all original studies that investigated the use of PLEX for the treatment of IgAN or HSP with associated RPGN (with or without crescents). Both native and transplanted kidneys affected by IgAN were included. The systematic literature review was individually conducted by two investigators (P.K. and S.T.) using the search strategy as described in the online Supplementary Data. The search strategy included the terms "plasmapheresis or apheresis or plasma exchange" AND "IgA nephropathy or Henoch Schönlein purpura". A manual search for additional potentially relevant studies using the references of the included articles was also performed. No language limitation was applied. Any differing decisions were resolved by mutual consensus. This study was conducted in agreement with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) Statement as described in the online Supplementary Data.

Selection Criteria
Eligible studies included case reports, case series, and cohort studies that evaluated the role of PLEX in the treatment of IgAN or HSP with associated RPGN (with or without crescents). Studies had to report the following outcomes: remissions, relapses, degree of proteinuria, and serum creatinine/estimated glomerular filtration rate. The exclusion criteria included studies that primarily reported other treatment outcomes. Inclusion was not restricted by study size. Remission was determined by the reduction of proteinuria based on each article. In general, complete remission (CR) was defined as proteinuria of less than 0.3 g per 24 h, and partial remission (PR) was defined as a reduction of proteinuria between 0.3 and 3.5 g per 24 h and a 50% reduction from baseline. The quality of each study was evaluated by the investigators using the validated methodological index for non-randomized studies (minors) quality score.

Data Abstraction
A structured data collection report was adopted to derive the following information from the included studies: first author's name, publication year, country of reporting, demographic data, kidney biopsy features, treatment regimen for PLEX, other treatments given, native or transplanted kidney, the outcome of treatment, adverse effects encountered, and other accompanying disease which would affect the kidneys or would cause alveolar hemorrhage and thrombotic microangiopathy. To ensure precision, this data extraction process was independently performed by three investigators (B.N., P.A, and W.C.)

Results
After excluding duplications, the search strategy retrieved 1382 potentially relevant articles. After excluding 1275 articles based on the titles and abstracts not fulfilling the inclusion criteria (as described in Figure 1, 107 articles underwent full-length review. An additional 69 articles were excluded due to either a lack of outcome of interest or poor methodological quality. Consequently, 38 studies (29 case reports and 9 case series) with 102 patients were enrolled in the analysis. These 38 studies underwent an assessment of methodological quality utilizing the tool published by Murad et al. in 2018 [20]. The literature retrieval, review, and selection process are shown in Figure 1. The characteristics of all included studies are shown in Tables 1 and 2. The assessment of methodological quality for each included study is shown in Supplementary Tables S1 and S2.        Plasma exchange (6 treatments in 2 weeks followed by weekly PLEX for at least 2 weeks).

Steroids Cytoxan
All patients saw improvement in serum creatinine and urine abnormalities, but 3 patients eventually developed ESKD at long-term follow up.
No correlation between urine abnormalities, HTN, sCr, and histological features was found.
No clinical or histological parameter was significantly different between patients in the treatment group.

Effect of Plasmapheresis in Patients with Transplanted Kidneys with IgA Nephropathy
The analysis of the included studies found that only five patients were reported to receive PLEX for IgAN with RPGN in transplanted kidneys. Only one of these five kidney transplant recipients (20%) achieved remission, while the remaining four (80%) developed ESKD.

Alveolar Hemorrhage with IgA Nephropathy
Pulmonary renal syndrome with IgA nephropathy was reported in the included studies. Eleven out of the 84 included patients who were treated with PLEX for IgAN had an alveolar hemorrhage, and the majority of these (10/11) patients had improvement or resolution of pulmonary symptoms after treatment. Four of these patients had a concomitant glomerular disease with IgA nephropathy, including two patients with ANCA positivity, one with Anti GBM antibody positivity, and one with hemolytic uremic syndrome. The role of plasma exchange in pulmonary-renal syndromes for Anti GBM and ANCA vasculitis is well established, and PLEX has been successfully utilized in atypical HUS. Some of the included patients did have concomitant illness along with IgAN (as noted above in Tables 1 and 2) but overall appeared to have a good response in terms of pulmonary symptoms.

Adverse Events of Plasmapheresis
Infectious complications (8 of 102 patients) were the most commonly reported adverse event. All patients who developed infectious complications were on immunosuppressants, including steroids, mycophenolate, and cyclophosphamide. These infectious complications included catheter-associated sepsis, septic shock, bacterial pneumonia, cytomegalovirus (CMV) viremia, pneumocystis (PJP) pneumonia, influenza A, herpes zoster, and Rothia bacteremia. There were also reports of volume overload and cardiac arrest attributed to hypocalcemia and anaphylaxis. One patient developed an itchy rash following FFP that resolved after treatment with steroids and chlorpheniramine. Another patient developed femoral vein thrombosis, and one patient had PLEX catheter dislodgment. Reported adverse events are summarized in Table 3.

Discussion
This systematic review demonstrates the potential role of PLEX in the treatment of rapidly progressive/crescentic IgAN and HSP. Plasmapheresis's removal of immune complexes may have a role in the treatment of aggressive forms of IgA and HSP.
This comprehensive analysis demonstrated a larger benefit with PLEX on HSP compared to IgAN patients (76.3% vs. 42.1% of patients achieved remission, respectively). The underlying reason for this variance is unclear, but it could possibly be related to the underlying pathophysiological differences between these diseases [59]. This study also demonstrated significant heterogeneity in treatment regimens, but a common theme was that early initiation of PLEX was associated with improved renal outcomes. In the Gianviti et al. case series, the five patients who did not achieve remission (reduction of proteinuria to less than 3.5 g per 24 h) did not start PLEX until 2 or more months after the onset of symptoms [40]. In contrast, nine of the ten patients who achieved at least partial remission and had stable kidney function over a follow-up period of 24-72 months had initiated plasmapheresis treatment within 1 month of symptom onset. This relationship was redemonstrated in the Shenoy et al. case series where all patients that initiated PLEX within 2 weeks of symptom onset achieved remission, whereas the single patient who delayed treatment until 2 months after symptom onset ultimately developed ESKD and required a kidney transplant [41]. The findings of this review support the KDIGO 2021 clinical practice guidelines that suggest treating RPGN due to IgA vasculitis similarly to ANCA-associated vasculitis where PLEX is sometimes utilized [2].
IgAN with pulmonary manifestations is rare, but all patients that presented with alveolar hemorrhage in our systematic review had significant improvement or resolution of pulmonary symptoms following PLEX. Although kidney outcomes following PLEX in IgAN with RPGN were ambivalent, these results support the use of PLEX in treating severe extra-renal manifestations of IgAN. PLEX has also been shown to have excellent outcomes in treating extra-renal manifestations of ANCA-associated vasculitis, which highlights the potentially shared pathophysiology between these two diseases [19].
Infectious complications arose in nearly 10% of analyzed patients. While most of the patients were already at high risk of infection due to adjunctive immunosuppression, carefully weighing risks-benefits prior to the initiation of PLEX and monitoring for infection is recommended given the impact of PLEX on both the immune system and antibiotic pharmacokinetics [60].
Crescentic disease was seen in most patients included in this analysis, regardless of IgAN or HSP status. Crescent formation is thought to be related to complement activation; prior studies have highlighted a positive correlation between urinary C4d and the degree of crescent development [61]. A crescent score was added to the Oxford MEST for grading IgAN severity in 2016 after their working group identified an inverse correlation between the degree of crescentic disease and kidney outcome [62]. However, the 2021 KDIGO guidelines recommended that the presence of crescents should not dictate therapy unless there is a concomitant change in eGFR [2]. The analysis failed to demonstrate an association between the degree of crescentic disease and kidney outcomes. Further randomized controlled trials and prospective data are needed to clarify the clinical utility of MEST-C and PLEX.
To the authors' knowledge, this is the first systematic review of the use of PLEX for rapidly progressive and/or crescentic IgA nephropathy. However, there are several limitations. First, the majority of the published studies are case reports and case series, which often limits data to evaluate long-term outcomes. The literature search for this systematic review did not reveal any published randomized clinical trials that evaluated PLEX in rapidly progressive and/or crescentic GN with IgA nephropathy. Second, the included studies were heterogeneous in terms of the onset of treatment, treatment regimen, patient inclusion, and duration of follow-up. Finally, despite a comprehensive review, only a few kidney transplant patients were included, so the findings of this study may not be generalized for transplant patients.

Conclusions
In summary, this systematic review supports the benefit of plasmapheresis in HSP with RPGN, and it suggests a possible benefit of plasmapheresis in IgAN with RPGN. Randomized controlled trials are needed to further establish the role of plasmapheresis in rapidly progressive IgA nephropathy.